MI is the leading cause of death in the developed world, including the United States. In 2005 over 8.1 million Americans had an MI; 30% died before reaching hospital and 10% died after hospitalization. It is the 70% who reach hospital that we believe we can help - a million lives in the balance and an improved quality of life for millions more - in the US alone. The goal of these studies is to bring a novel therapeutic approach to myocardial infarction (MI) and ischemia-reperfusion (IR) wound healing to the clinic. The approach is both strikingly effective and exactly contrary to conventional wisdom. In a murine model we have shown that temporary depletion of dendritic cells (DC) during MI wound healing results in an 80% improvement in cardiac function and a 65% reduction in MI size. Cardiac function is the greatest determinant of survival post-MI. We will continue the development of this seminal discovery into a human therapy by completing preclinical murine safety and efficacy testing in our proprietary transgenic (TG) mouse model. The product is a human mannose receptor (hMR) targeted fusion protein designed to deplete DC post-MI. The previously unrecognized role for DC in MI wound healing is noteworthy for at least two reasons. First, immunologists and cardiologists have conventionally thought that depletion of DC post-MI would result in catastrophe: i.e. weakened tissues (cardiac rupture) and no new vasculature. Second, the beneficial effect of DC depletion is startling in its magnitude (up to 80% improvement in heart function vs. controls). A treatment that temporarily depletes DC is nothing short of a paradigm shift that we believe will lead to a sharp reduction in mortality and profound improvements in the lives of patients. In Phase I, we demonstrated safety and efficacy of a hMR-targeted immunotoxin in a highly human- relevant murine model. In Phase II we will complete pre-clinical testing through rigorous dose optimization as well as safety and efficacy studies in murine models and human histology and blood work (in vitro). The compelling safety and efficacy results combined with the lack of a suitable second species means the work described herein is expected to be sufficient for a successful IND application. We are engaged in continuing discussions with both clinicians and the FDA regarding this pre-clinical path as well as the design of a Phase I clinical trial. We will bring the drug to market in collaboration with or strategic partners. Initial results suggest that this strategy may lead to a sharp reduction in mortality and profound improvements in the lives of victims of MI. PUBLIC HEALTH RELEVANCE: Heart attacks are the leading cause of death in the developed world. By temporarily depleting a cell type commonly associated with inflammatory and immune responses, we have been able to dramatically improve heart function after a heart attack in mice. The overall goal of this project is to advance these results toward a drug that will help humans.